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Localized modulation of tissues and cells to enhance therapeutic effects including renal denervation

Active Publication Date: 2013-09-26
MERCATOR MEDSYST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention relates to improving the effectiveness of therapeutic agents in treating disease by modifying the local tissue environment to enhance the therapeutic index of the agents. Specifically, the invention involves the use of pH modulators to enhance the activity of guanethidine in reducing sympathetic nerve activity in the kidneys and improving blood pressure control. The invention also includes the use of hypertonic or hypotonic solutions to enhance cellular uptake of therapeutic agents, as well as the formulation of guanethidine in alkaline solutions to improve its effectiveness in denervating nerves. The invention also involves delivering therapeutic agents into specific zones in the body to improve their therapeutic index.

Problems solved by technology

While it has been published that pH differences may alter drug effects in cell culture assays, the localized or regionalized modification of pH within the body to enable more rapid drug uptake, more rapid clearance, or improved effect has not been attempted.

Method used

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  • Localized modulation of tissues and cells to enhance therapeutic effects including renal denervation
  • Localized modulation of tissues and cells to enhance therapeutic effects including renal denervation
  • Localized modulation of tissues and cells to enhance therapeutic effects including renal denervation

Examples

Experimental program
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Effect test

example 1

In Vitro Response of Nerve and Smooth Muscle Cells to pH and Guanethidine Monosulfate Concentration

[0173]Guanethidine Monosulfate and pH interaction studies were performed on sympathetic neuronal and perivascular and vascular cell types. The following cell types were examined:[0174]SH-SY5Y: Human neuroblastoma line SH-SY5Y, plated but uninduced[0175]Induced SH-SY5Y: SH-SY5Y induced with retinoic acid to differentiate into neurite growing sympathetic nerve cells[0176]rPC-12: Adherent-type rat PC-12 cells, plated but uninduced[0177]Induced rPC-12: PC-12 induced with NGF to differentiate into neurite growing sympathetic nerve cells[0178]Rat SCG: Primary rat superior cervical ganglia cells[0179]hAoSMC: Primary human aortic smooth muscle cells

[0180]Cells were treated with 0, 1, 10, 100 or 1000 μg / mL guanethidine monosulfate (GNT), or 10 μg / mL GNT and 17% IsoVUE370, at pH 6.3 and pH 9.3. At 4 h and in replicate cultures at 24 h, the medium was replaced with regular growth medium with the ...

example 2

Animal Study and Follow Up Studies

[0210]Guanethidine tested in certain preclinical studies showed that there was nerve damage, however the form of the guanethidine tested in these studies was guanethidine hemisulfate. Later testing in an animal study using guanethidine monosulfate at an unbuffered pH (6.3 or less) produced safe results, but failed to show significant denervation. Buffering of guanethidine monosulfate to a pH in the ranges successfully shown to denervate using guanethidine hemisulfate is possible. Titration experiments as shown in FIG. 20B depict how guanethidine monosulfate can be buffered with sodium hydroxide to achieve the same pH as the guanethidine hemisulfate used in the studies with successful denervation. This alkaline buffered form of guanethidine monosulfate may be used to denervate nerves by delivery of such composition to tissue surrounding such nerves. Such delivery may be transluminal, for example using devices noted herein, or may be delivered in anot...

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Abstract

Pharmaceutical preparations, compositions, systems, and devices including medical devices and diagnostic or therapeutic agents, and methods to treat disease by modification of local tissue environment to modulate the therapeutic index of locally or systemically delivered therapeutic or diagnostic agents. Improved ability to reduce sympathetic nerve activity in the adventitia and perivascular tissues around arteries and veins in the body. Modulation of the local tissue environment around an artery to enable more effective denervation with or without a therapeutic agent. Modulation may include adjustment of the pH of the tissue.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of U.S. Provisional Application No. 61 / 548,822, filed Oct. 19, 2011, which application is incorporated herein by reference in its entirety.BACKGROUND AND SUMMARY OF THE INVENTION[0002]Pharmaceutical and biotherapeutic agents interact with cells differently depending on the local physiologic conditions of the tissue in which they are delivered or taken up. For example, pH changes can lead to differences in the uptake of drugs into cells due to membrane permeability or polarization of the pharmaceutical agent, among other reasons.SUMMARY OF THE INVENTION[0003]While it has been published that pH differences may alter drug effects in cell culture assays, the localized or regionalized modification of pH within the body to enable more rapid drug uptake, more rapid clearance, or improved effect has not been attempted.[0004]Provided herein are compositions, methods, devices, and systems that generate this effec...

Claims

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Application Information

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IPC IPC(8): A61K31/395
CPCC07D295/13A61K31/395A61P11/00A61P25/00A61P25/02A61P29/00A61P5/50A61P9/04A61P9/12
Inventor SEWARD, KIRK P.
Owner MERCATOR MEDSYST
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